ES2323127T3 - TRANSDERMAL POSOLOGICAL FORM THAT INCLUDES AN ACTIVE AGENT AND A SALT FORM AND A FREE BASE FORM OF AN ANTAGONIST. - Google Patents

Abstract

This invention relates to a tamper-resistant transdermal dosage form comprising an active agent, such as an opioid, or a pharmaceutically acceptable salt thereof, a free base of an adverse agent, such as an opioid antagonist, and a pharmaceutically acceptable salt of an adverse agent, such as an opioid antagonist. The transdermal dosage form allows an effective amount of the active agent, or a pharmaceutically acceptable salt thereof, to be transdermally administered to an animal. The invention further relates to methods for treating or preventing pain in an animal comprising contacting the skin of an animal in need thereof with the transdermal dosage form of the invention for an amount of time sufficient to treat or prevent pain.

Description

Transdermal dosage form comprising a active agent and a salt form and a free base form of a antagonist.

1. Scope of the invention

The present invention relates to forms Transdermal dosages useful to prevent or deter abuse of an active pharmaceutical agent such as an opioid. The The present invention also relates to dosage forms transdermal resistant to misuse comprising an active pharmaceutical agent or a pharmaceutically acceptable salt thereof and an active pharmaceutical agent antagonist, the antagonist comprising both an adverse agent in the form of free base as a pharmaceutically acceptable salt of antagonist. In particular, the present invention relates to Transdermal dosage forms resistant to use unduly comprising a pharmaceutically opioid or salt acceptable thereof, a free base opioid antagonist and a pharmaceutically acceptable salt of an opioid antagonist.

2. Background of the invention

The transdermal dosage forms are convenient to provide a large number of different agents therapeutically effective among which are included, although without limiting nature, pain relievers such as pain relievers opioids Although not limited to these, the typical Opioid analgesics include members of the group consisting of of fentanyl, buprenorphine, etorphins and other narcotics high power. Although not limited to these, other agents therapeutically effective that can be provided using a form Transdermal dosage include members of the group consisting of of antiemetics (such as scopolamine), agents cardiovascular (such as nitrates and clonidine), hormones (such as estrogen and testosterone), nicotine, vitamins and Dietary supplements.

The most common transdermal dosage form is a diffusion-controlled transdermal system (particularly in the form of a patch) that uses either a fluid reservoir system or an adhesive drug-like matrix system. Although not limited to these, other transdermal dosage forms include members of the group consisting of gels, lotions, ointments, transmucosal systems and devices, and iontophoretic input systems (by electrodiffusion). See, for example, US Patent No. 4,626,539 issued to Aungst et al ., Which discloses a pharmaceutical composition that is supposedly useful for the transdermal delivery of an opioid to the mammalian circulatory system; US Patent No. 4,806,341 issued to Chien et al ., which discloses transdermal absorption dosage units comprising a liner layer, an adhesive polymer layer and an adjacent layer of a solid polymer matrix containing an antagonist or morphinan narcotic analgesic and dermal penetration enhancers; and US Patent No. 5,069,909 issued to Sharma et al ., which discloses methods for the sustained administration of buprenorphine using a transdermal delivery from a patch of laminated composite.

The transdermal dosage forms are particularly useful for timed release and sustained release of active agents. However, many ways Dosages, and particularly those intended for release timed and sustained active agents, contain large amounts of active agents, often in an amount that is many times higher than the actual dose that is absorbed or provided. Additionally, users sometimes remove the patch before the expiration of the recommended period of use. Thus, having been the device used and removed by the user, there is often a significant amount of the active agent in the dosage form. So much the unused dosage form as the part of active agent that remains in the dosage form after use are potentially susceptible to misuse or intentional abuse or involuntary, particularly if the active agent is a narcotic or a controlled substance For example, dosage forms used not at all and that contain leftover opioids can be improperly used by chewing or extracting by Part of a drug abuser. Even the careful elimination of the dosage forms used may not be completely effective for prevent abuse, particularly in cases of compliance incomplete or partial of the optional prescription by the patient.

US Patent No. 5,830,497 issued to Yamanaka et al . discloses a medicated plaster composition as a dosage form for percutaneous absorption, the composition containing either (1) a basic drug and an acid substance, (2) a salt of a basic drug and a basic substance, or (3) a basic drug and a salt of a basic drug. The patent does not address the problem of active drug abuse, and does not address the use of antagonists to prevent such abuse.

US Patent No. 5,804,215 issued to Cubbage et al . discloses a removal system for a transdermal patch containing a medicament, such as nicotine, said removal system comprising a flexible substrate, tear-resistant and coated with adhesive. The used transdermal patch allegedly adheres to the substrate in order to encapsulate the transdermal patch and deter any attempt to gain access to it. Rubber-based adhesives are indicated as preferred.

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US Patent No. 5,149,538 issued to Granger et al . discloses a transdermal patch comprising an opioid and an antagonistic substance that are separated by an impermeable barrier. The antagonistic substance is supposedly capable of being released by the patch when ingested or practically immersed in a solvent.

US Patent No. 5,236,714 issued to Lee et al . discloses a composition comprising a substance susceptible to abuse and an antagonist for the substance susceptible to abuse. Supposedly a mixture of oral and parenterally active antagonists can be used. The patent does not address the problem of extraction using different solvent systems, and does not describe the use of a plurality of antagonists that have different solubilities.

It is still a major health problem the abuse or involuntary misuse of dosage forms transdermal Thus, there is still a need in the art of forms Enhanced transdermal dosages that are effective in preventing the abuse of a therapeutic agent such as an opioid or a salt pharmaceutically acceptable thereof, but nevertheless are Useful to provide it.

3. Brief exposition of the invention

In one embodiment, the present invention is directed to transdermal dosage forms comprising a active agent, a pharmaceutically acceptable salt of an antagonist and an antagonist in the form of a free base.

In another embodiment, the present invention is directed to transdermal dosage forms comprising a active agent, a pharmaceutically acceptable salt of an antagonist and an antagonist in the form of a free base, in an amount enough to inhibit at least one biological effect of the agent active.

In another embodiment, the present invention is directed to a transdermal dosage form comprising a analgesically effective amount of an opioid or salt pharmaceutically acceptable thereof (hereafter "Opioid"), an opioid antagonist in the form of a free base (hereinafter "Free Antagonist Base"), and a salt Pharmaceutically acceptable opioid antagonist (from here on forward "Antagonist Salt"), in an amount sufficient to inhibit the euphoric effect of Opioid.

The invention is further directed to methods that are to treat or prevent pain in an animal and understand the step of putting the skin of an animal that needs it in contact with a transdermal dosage form comprising a analgesically effective amount of an Opioid, a Free Base Antagonist and an Antagonist Salt in an amount sufficient to inhibit the euphoric effect of Opioid, and where the setting in contact takes place for a period of time Enough to treat or prevent pain.

The present may be more fully understood invention referring to the following figures, to the following detailed description and the following examples, with the which is intended to exemplify non-limiting realizations of the invention.

4. Brief description of the drawings

Fig. 1 is a schematic cross section in a reservoir-type transdermal dosage form.

Fig. 2 is a schematic cross section in a polymer matrix type transdermal dosage form.

Fig. 3 is a schematic cross section in a transdermal dosage form in drug-type adhesive.

Fig. 3A is a cross section schematic of an alternative transdermal dosage type Adhesive drug.

Figs. 4 and 5 are graphs that represent the Amount of Opioid or Antagonist extracted referred to time.

5. Detailed description of the invention

The present invention relates to a form transdermal dosage that is useful for administration transdermal of an active agent, such as an Opioid, to an animal, and to methods that are to treat or prevent pain in an animal and understand the step of putting on the skin of an animal that has need for it in contact with the transdermal dosage form of the invention for a sufficient amount of time to treat the patient, such as to treat or prevent pain. In one embodiment, the transdermal dosage form of the present invention comprises an active agent, an adverse agent in the form of a free base and a salt of an adverse agent. In one embodiment, a salt of an adverse agent is present in an amount enough to inhibit at least one biological effect of an agent active when it and the adverse agent in the form of a base free are administered (by routes such as buccal, nasal, sublingual, parenteral, rectal and / or vaginal) to an animal, and more preferably a human. In another embodiment, an agent adverse in the form of a free base is present in an amount enough to inhibit at least one biological effect of an agent active when it and the salt of an adverse agent are administered (by routes such as buccal, nasal, parenteral, rectal and / or vaginal) to an animal, and more preferably a human. In a further embodiment, a adverse agent in the form of a free base and the salt of an agent adverse are expected in a total amount sufficient to inhibit the less a biological effect of an active agent when the same, the adverse agent in the form of a free base and the salt of an agent Adverse are administered (by routes such as buccal, nasal, the sublingual, parenteral, rectal and / or vaginal) to an animal, and more preferably a human. In a further embodiment, a adverse agent in the form of a free base and an agent salt adverse are expected in a total amount sufficient to inhibit the less a biological effect of an active agent when the form Transdermal dosage is subject to abuse or misuse. In other embodiment, an Antagonist Salt is present in an amount enough to inhibit the euphoric effect of an Opioid when the same and the Free Antagonist Base are administered (via such as oral, nasal, sublingual, parental, rectal and / or vaginal) to an animal, and more preferably to a human. In another embodiment, an Antagonist Salt is present in an amount sufficient to inhibit the euphoric effect of a Opioid when it and the Antagonist Free Base are administered (by routes such as buccal, nasal, parental, rectal and / or vaginal) to an animal, and more preferably to a human. In a further embodiment, an Antagonist Free Base and an Antagonist Salt is expected in a total amount sufficient to inhibit the euphoric effect of an Opioid when the same, the Base Free Antagonist and Antagonist Salt are administered (by routes such as buccal, nasal, sublingual, parenteral, rectal and / or vaginal) to an animal, and more preferably to a human. In a further embodiment, an Antagonist Free Base and an Antagonist Salt is expected in a total amount sufficient to inhibit the euphoric effect of an Opioid when the form Transdermal dosage is subject to abuse or misuse.

When put in contact with the skin of a animal, the transdermal dosage form allows administration transdermal of an Opioid, but either (a) allows the transdermal administration of only a quantity of a Base Free Antagonist or Salt Antagonist (each being a "Antagonist") that is ineffective in inhibiting the effect Opioid analgesic, or (b) does not allow administration transdermal of an Antagonist. But if the dosage form transdermal of the invention is used to provide an Opioid by a route other than transdermal, such as a buccal route, nasal, oral, parenteral, rectal and / or vaginal, or if the form Transdermal dosage is subject to abuse or misuse, then one of the antagonists or both inhibits the effect Euphoric Opioid. Preferably, the dosage form transdermal will inhibit the euphoric effect of an Opioid if the device is used differently from the transdermal either before or after being the device used by an animal to Treat or prevent pain.

The transdermal dosage form of the invention is resistant to misuse because if a Abuser tries to extract or separate an Opioid from the dosage form transdermal and self-administer the Opioid by another route such as, although without limitation, the oral, parenteral, nasal or buccal, rectal or vaginal, that is, by a route of administration that can result in a rapid euphoric outburst, also known as the "high", which abusers may prefer, the Abuser would self-administer an amount of an Antagonist together with the Opioid, the amount of Antagonist being effective for inhibit the euphoric effect of Opioid.

For example, if an abuser tries to extract a Opioid of the transdermal dosage form by putting it in a solvent, including saliva, then it would also be extracted an amount of an antagonist, forming a mixture of the Opioid and the antagonist. The Free Antagonist Base generally presents greater solubility, and in an embodiment greater bioavailability, in non-aqueous solvents than in aqueous solvents, while a Antagonist salt generally presents greater solubility, and in a greater bioavailability, in aqueous solvents than in non-aqueous solvents. So, if an abuser tries to extract a Opioid of the transdermal dosage form by using a non-aqueous solvent such as an ether or an alcohol, a Free Base Antagonist would be extracted along with the Opioid, forming a mixture of the Opioid and the Antagonist. Alternatively, if an abuser try to extract an Opioid from the transdermal dosage form through the use of an aqueous solvent such as water or saliva, a Antagonist salt would be extracted along with the Opioid, forming a mixture of Opioid and Antagonist.

If a mixture of an Opioid and an Antagonist is administered by a route other than the transdermal route planned, then at least one Antagonist would exert its effect antagonist to inhibit the euphoric effect of Opioid.

The invention further relates to methods that are to treat or prevent pain in an animal and understand the step of administering transdermally to an animal that has need for it an analgesically effective amount of a Opioid, using a transdermal dosage form of the invention.

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5.1 Definitions

In the sense in which it is used in the present, the phrase "transdermal dosage form" means any device that when put in contact with the skin of a animal can transdermally provide an effective amount of any biologically active agent, such as an agent Pharmacist, such as an Opioid, through the skin of the animal.

In the sense in which they are used in the present, the expressions "dosage form" and "device of contribution "are synonymous and interchangeable.

Any reference made here to any Pharmaceutical agent including, but not limited to, a an active agent, an adverse agent, an opioid agonist or a opioid antagonist, unless otherwise indicated will include any pharmaceutically acceptable form of such a pharmaceutical agent, such as the free form, any form of salt pharmaceutically acceptable, all forms of pharmaceutically acceptable base, all pharmaceutically acceptable hydrate, all pharmaceutically solvate acceptable, all stereoisomer, all optical isomer, as well as all prodrug of such pharmaceutical agent and all pharmaceutically analogous active of such a pharmaceutical agent, and mixtures of any of the above.

In the sense in which it is used here, the phrase "active agent" refers to a pharmaceutical agent, an agent therapeutic, a drug and / or an agonist that causes an effect biological when absorbed in sufficient quantity in the torrent blood of a patient.

In the sense in which it is used here, the phrase "adverse agent" refers to a pharmaceutical agent, a drug and / or an antagonist that partially or completely prevents, denies, decreases, delays or reverses at least one biological effect of active agent present in the dosage form, as is p. ex . a euphoric effect, or produces one or more unpleasant physiological reactions, such as e.g. ex . vomiting, nausea, diarrhea or bad taste, when absorbed in sufficient quantity into a patient's bloodstream.

In the sense in which they are used in the present, the expressions "opioid" or "opioid agonist" they refer to an active agent that has properties of the type of those of opium or morphine when absorbed in amounts enough in a patient's bloodstream. Agonists opioids are fixed, optionally stereospecifically, to any or several of several opioid receptor subspecies, and They produce agonist activity.

In the sense in which it is used herein, the phrase "opioid antagonist" refers to an adverse agent that partially or completely prevents, denies, decreases, delays or reverses at least one biological effect of an opioid agonist, such as p . ex . a euphoric effect, when absorbed in sufficient quantities into a patient's bloodstream.

In the sense that it is used herein, the phrase "pharmaceutically acceptable salt" is a salt made from an acid and the basic nitrogen group of an opioid. Although not limited to these, preferred salts include members of the group consisting of sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, citrate salts acid, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, glubionate and pamoate (ie , 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)). The term "pharmaceutically acceptable salt" also refers to a salt prepared from an opioid having an acid functional group, such as a carboxylic acid or sulfonic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Although not limited to these, suitable bases include members of the group consisting of alkali metal hydroxides such as sodium, potassium and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines such as mono-, di-, or unsubstituted or hydroxy-substituted trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris- (2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl ) methylamine, N, N, -di-lower alkyl-N- (hydroxy lower alkyl) -amines, such as N, N, -dimethyl-N- (2-hydroxyethyl) amine, or tri- (2-hydroxyethyl) amine ; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and similar substances.

In the sense in which it is used in the present, the word "animal" includes, although without character limiting, to a cow, a monkey, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, a rabbit and a guinea pig, and is more preferably a mammal, and most preferably a human.

In the sense in which it is used in the present, the phrase "pain treatment" or "treat the pain "includes improvement of pain or cessation of pain in an animal.

In the sense in which it is used in the present, the phrase "pain prevention" or "prevent pain "includes the avoidance of pain initiation in a animal.

5.2 The transdermal dosage form

Any device known to those skilled in the art for transdermally providing a therapeutic agent, and particularly an Opioid, to an animal can be used for the transdermal dosage form of the invention. For example, the transdermal dosage form may be a reservoir type transdermal dosage form, a polymer matrix type transdermal dosage form, or a drug-like transdermal dosage form in adhesive ( see, eg , HS Tan et al ., Pressure Sensitive Adhesives for Transdermal Drug Delivery Systems, in PSTT 2 (2): 60-79 (1999)). The transdermal dosage form is designed in such a way that, when brought into contact with the animal's skin, an analgesically effective amount of the active therapeutic agent, such as an Opioid, is transdermally administered to the animal. But, since said transdermal dosage form is in contact with the skin of an animal, an Antagonist Free Base and an Antagonist Salt remain in the transdermal dosage form and are not administered to the animal, or the animal is administered in an amount that is insufficient to inhibit the analgesic effect of the active agent.

A type transdermal dosage form reservoir typically comprises a reservoir, which is usually  a liquid and is located between a waterproof liner film and a speed controlling membrane that is covered with a pressure sensitive adhesive layer that remains in contact with the skin. He reservoir, which may be a solution or a dispersion, comprises an active agent such as an Opioid, an Antagonist Free Base and an antagonistic salt. The transdermal dosage form is supported For the waterproof lining material and the adhesive surface is protected by a non-stick coating. Although not left limited to these, suitable lining materials include members of the group consisting of polyethylene, derivatives of polyethylene, polypropylene, polyesters, polyurethanes, fibers Nylon and natural fibers. Although not limited to these, the Suitable non-stick coatings include members of the group consisting of conventional nonstick coatings comprising a sheet material such as a polyester sheet, a polythene sheet, a polystyrene sheet or paper coated with polyethylene and with a suitable coating made to fluoropolymer or silicone base. To manage an active agent  such as an Opioid, the coating is removed nonstick to expose the adhesive pressure-sensitive, and the pressure-sensitive adhesive is put in contact with the skin. The active agent is susceptible to permeating the membrane speed controller and passes through it and the adhesive, comes into contact with the skin, and then goes through the skin. The contribution rate of an active agent such as an Opioid  is partially controlled by the speed at which the agent active passes through the speed controlling membrane. Preferably, the pressure sensitive adhesive does not affect Adverse to the rate of contribution and does not react chemically with the active agent. The speed of contribution is such that it is contributed to the animal an analgesically effective amount of an active agent such As an Opioid In contrast to an active agent, such as a Opioid, an Antagonist, that can be present anywhere in the reservoir, preferably it does not cross the membrane speed controller, or, if so, it does in an amount that is insufficient to inhibit the effect analgesic of the active agent.

Fig. 1 represents an embodiment of a reservoir transdermal dosage form. The dosage form transdermal 10 comprises a reservoir 11, which is typically in form of a solution or a dispersion 12 and has dispersed in the same an active agent, such as Opioid 13, a Free Base Antagonist 14, and an Antagonist Salt 14a. Reservoir 11 is disposed between a waterproof liner film 15, a membrane speed controller 16 and a pressure sensitive adhesive 17. A nonstick coating 18 is applied to the adhesive layer pressure sensitive 17 and is removed before use. In one embodiment, the  Opioid 13 and Antagonists 14, 14a, of which at least one it is a Free Antagonist Base 14 and at least one is a Salt 14th antagonist, they are scattered throughout the reservoir, although not a uniform dispersion is necessary.

The polymer matrix type design constitutes a variation of the reservoir type transdermal dosage form. In the polymer matrix design, an active agent such as a Opioid and Antagonists are dispersed in a matrix of polymer that partially controls the rate of contribution of the agent active. Similarly to what happens in the case of type design liquid reservoir, the reservoir constituted by the matrix of Polymer is supported in a waterproof lining layer. Instead of having a continuous layer of adhesive, however, the type design polymer matrix usually includes a peripheral ring of adhesive that is located around the edge of the patch. A non-stick coating protects the adhesive surface and the polymer matrix surface. To administer an agent active such as an Opioid, the coating is removed non-stick to expose the polymer matrix and to the pressure sensitive adhesive ring, and the device is put on Skin contact. The adhesive ring holds the device against the skin, whereby the polymer matrix is directly in contact with the skin. When the polymer matrix is in contact with the skin, an active agent such as an Opioid diffuses of the polymer matrix, comes into contact with the animal's skin, and passes through the skin. The contribution rate of Antagonists is partially controlled by the speed of diffusion of the Antagonists out of the polymer matrix. The contribution rate is such that the animal is given a analgesically effective amount of an active agent such as a Opioid Antagonists, who can be present in any site in the polymer matrix, on the other hand they do not diffuse of the polymer matrix, or, if diffusion occurs, they leave in an amount that is insufficient to inhibit the effect analgesic of the active agent.

Fig. 2 represents a typical embodiment of the invention in the form of a type transdermal dosage form polymer matrix The transdermal dosage form 20 comprises a reservoir 21 which is in the form of polymer matrix 22 which has dispersed therein an active agent such as Opioid 23, a Free Base Antagonist 24 and an Antagonist Salt 24a. In a realization, Opioid 23 and Antagonists 24, 24a are dispersed throughout the polymer matrix, although it is not necessary a uniform dispersion Polymer matrix 21 is supported on a waterproof lining layer 25 and has a peripheral ring of adhesive 26 located around the edge of the patch. A lining Nonstick 28 is applied to the peripheral ring of adhesive 26 and to polymer matrix 22 and is removed before use.

The drug-like transdermal dosage form in adhesive comprises an active agent such as an Opioid, a Base Free Antagonist and an Antagonist Salt that are dispersed directly in a matrix of pressure sensitive adhesive. The matrix of adhesive is typically supported on the upper side with a waterproof lining film and on the side facing the skin with a waterproof non-stick coating. For administering an active agent, such as an Opioid, proceeds to remove the non-stick coating to leave the discovered the adhesive matrix, and puts the device in Skin contact. The adhesive matrix serves to adhere the device to the skin and typically to control the speed of contribution of an active agent such as an Opioid. Analogously to what what happens in the case of the polymer matrix type design, the design Adhesive drug type allows an active agent to exit by diffusion of the adhesive matrix, come into contact with the skin of the animal and pass through the skin. The contribution rate of a active agent such as an Opioid is partially determined by the diffusion rate of the active agent out of the matrix of adhesive. The speed of contribution is such that it is contributed to the animal an analgesically effective amount of an active agent such As an Opioid Antagonists, who may be present in any place in the adhesive matrix, on the other hand they do not come out by diffusion of the adhesive matrix, or they do so in an amount which is insufficient to inhibit the analgesic effect of an agent active.

Fig. 3 represents a typical embodiment of the invention in the form of a type transdermal dosage form Adhesive drug. The transdermal dosage form 30 comprises a adhesive matrix 31 which has an agent dispersed throughout it active such as Opioid 32, an Antagonist Free Base 33 and a Antagonist salt 33a. In one embodiment, an Opioid 32 and the Antagonists 33, 33a are dispersed throughout the matrix of polymer, although a uniform dispersion is not necessary. Matrix of adhesive 31 is supported on a waterproof lining layer 34 and it has a waterproof non-stick coating 35 on the side that it faces the skin, said non-stick coating being Waterproof removed before use.

Fig. 3A represents another embodiment of the invention in the form of a drug-like transdermal dosage form in adhesive. The transdermal dosage form 40 comprises a first matrix of adhesive 41 that has a dispersed throughout it active agent such as an Opioid 42, and a second matrix of adhesive 43 that has a free base dispersed throughout it Antagonist and an Antagonist Salt 44, 44a. The first and second are separated by a barrier layer 45. Preferably, an Opioid and Antagonists are scattered throughout the matrix of adhesive, although a uniform dispersion is not necessary. He adhesive matrix system is supported on a lining layer of waterproof covering 46 and has a coating waterproof nonstick 47 on the side facing the skin, said waterproof non-stick coating being removed before use.

Reservoir-type, polymer matrix-type and drug-in-adhesive transdermal delivery systems are well known to those skilled in the art ( see, eg , HS Tan et al ., Pressure Sensitive adhesives for Transdermal Drug Delivery Systems, in PSTT 2 (2): 60-79 (1999), whose content is expressly incorporated herein by reference).

In the transdermal dosage form of the invention, any speed controlling membrane of those known to those skilled in the art can be used. In one embodiment, the membrane does not allow it to pass through the same any or any detectable amount of an Antagonist, particularly in those cases in which an Antagonist can pass through the skin of an animal. Although not limited to these, suitable materials for speed controlling membranes include members of the group consisting of polyethylene; Polypropylene; ethylene / propylene copolymers; ethylene / ethyl acrylate copolymers; ethylene / vinyl acetate copolymers; polyacrylates, polymethacrylates; silicone elastomers; medical grade polydimethylsiloxanes; neoprene rubber; polyisobutylene; chlorinated polyethylene; polyvinyl chloride; vinyl chloride-vinyl acetate copolymer; polymethacrylate polymer (hydrogel); polyvinylidene chloride; poly (ethylene terephthalate); butyl rubber; epichlorohydrin rubbers; ethylene vinyl alcohol copolymer; ethylene vinyl ethanol copolymer; silicone copolymers, such as, for example, polysiloxane-polycarbonate copolymers, polysiloxane-polyethylene oxide copolymers, polysiloxane-polymethacrylate copolymers, polysiloxane-alkylene copolymers ( eg , polysiloxane-ethylene-ethylene-ethylene-acylene-copolymers), (such as polysiloxane-ethylene-silane copolymers) and similar copolymers; cellulosic polymers, such as methyl cellulose or ethyl cellulose, hydroxypropylmethyl cellulose and cellulose esters; polycarbonates; polytetrafluoroethylene; starches, gelatin; natural and synthetic gums; any other natural or synthetic polymer or fiber (a); and combinations thereof.

The lining layer can be of any material suitable to be waterproof for compartment contents reservoir, of the polymer matrix or of the adhesive matrix. The Suitable materials for lining films are perfectly known to those skilled in the art and include, but without limiting nature, to the members of the group consisting of occlusive polymers such as polyurethane, polyesters such as poly (ethylene phthalate), polyetheramide, copolyester, polyisobutylene, polyesters, high and low density polyethylene, polypropylene, polyvinyl chloride, metallic and laminated folios of metal sheets and suitable polymer films.

Suitable materials for the polymer matrix are well known to those skilled in the art and include, but are not limited to, members of the group consisting of polyethylene; Polypropylene; ethylene / propylene copolymers; ethylene / ethyl acrylate copolymers; ethylene / vinyl acetate copolymers; silicone elastomers, and especially medical grade polydimethylsiloxanes; neoprene rubber; polyisobutylene; chlorinated polyethylene; polyvinyl chloride; vinyl chloride-vinyl acetate copolymer; polymethacrylate polymer (hydrogel); polyvinylidene chloride; poly (ethylene terephthalate); butyl rubber; epichlorohydrin rubbers; ethylene vinyl alcohol copolymer; ethylene vinyl ethanol copolymer; silicone copolymers, such as, for example, polysiloxane-polycarbonate copolymers, polysiloxane-polyethylene oxide copolymers, polysiloxane-polymethacrylate copolymers, polysiloxane-alkylene copolymers ( eg , polysiloxane-ethylene-ethylene-ethylene-acylene-copolymers), (such as polysiloxane-ethylene-silane copolymers) and similar copolymers; cellulosic polymers, such as methyl cellulose or ethyl cellulose, hydroxypropylmethyl cellulose and cellulose esters; polycarbonates; polytetrafluoroethylene; and combinations thereof. In one embodiment, the polymer matrix has a glass transition temperature below room temperature. The polymer can but does not necessarily have to have a degree of crystallinity at room temperature. Monomeric crosslinking sites or units may be incorporated into the polymers. For example, crosslinking monomers can be incorporated into polyacrylate polymers. Crosslinking monomers provide sites for crosslinking the polymer matrix after microdispersing the active agent, such as an Opioid, and an adverse agent, such as an Antagonist, in the polymer. Although not limited to these, known crosslinking monomers for polyacrylate polymers include members of the group consisting of polymethacrylic esters of polyols such as butylene diacrylate and dimethacrylate, trimethylolpropane trimethacrylate, and similar monomers. Other monomers that provide cross-linking sites include members of the group consisting of allyl acrylate, allyl methacrylate, diallyl maleate and similar monomers. In one embodiment, the polymer matrix does not allow any detectable amount or amount of an Antagonist to diffuse from it, particularly in those cases in which Antagonists can pass through the skin of an animal.

Materials that are suitable for the pressure sensitive adhesive matrix are perfectly known to those skilled in the art and include, but are not limited to, members of the group consisting of polyisobutylenes, polysiloxanes and polyacrylate copolymers (polyacrylic esters), adhesives made based on natural rubber / karaya rubber, hydrogels, hydrophilic polymers and polyurethanes such as those described in HS Tan et al ., Pressure Sensitive Adhesives for Transdermal Drug Delivery Systems, in PSTT 2 (2): 60-79 (1999) , whose description is incorporated herein by reference. The adhesive may further comprise modifying monomers, tackifier agents, plasticizers, fillers, waxes, oils and other additives to impart the desired adhesion properties. Id . In addition, one skilled in the art can easily achieve the desired adhesion properties by incorporating materials such as initiators, crosslinkers and comonomers. In one embodiment, the pressure sensitive adhesive matrix does not allow any detectable amount or amount of an Antagonist to diffuse from it, particularly in those cases in which the Antagonist can pass through the skin of an animal.

Piezosensitive adhesives that are preferred for use in the dosage forms of the invention include members of the group consisting of acrylates, polyisobutylenes, silicone polymers and mixtures thereof. Examples of polyisobutylene pressure-sensitive adhesive tools are described in Pat. No. 5,985,317 (Venkateshwaran et al .), The description of which is incorporated herein by reference. Examples of useful pressure sensitive silicone acrylate polymer adhesives and mixtures thereof are described in Pat. No. 5,474,783 (Miranda et al .), The description of which is incorporated herein by reference.

In general, the device size can vary from about 1 cm 2 to more than 200 cm 2, and is typically of about 5-50 cm 2. Methods are well known to those skilled in the art to manufacture transdermal dosage forms.

Although not limited to them, the examples of devices that are useful in methods and forms Transdermal dosage of the invention includes those who are described in U.S. Pat. No. 4,806,341, 5,069,909, 5,236,714, 5,240,711, 5,902,603, 5,718,914, 5,968,547, 6,162,456 and 6,344,212, whose descriptions are incorporated herein by reference

The transdermal dosage form may optionally comprise one or more penetration enhancers, which increase the rate at which an active agent such as an Opioid passes through the animal's skin. In one embodiment, the penetration enhancer does not improve the penetration of an Antagonist through the skin. In another embodiment, the penetration improver passes through the velocity controlling membrane or diffuses from the polymer matrix or the adhesive matrix, whereby it can establish contact with the animal's skin and improve penetration. of an active agent such as an Opioid through the animal's skin. Although not limited thereto, penetration enhancers that are suitable for use in the transdermal dosage methods and forms of the invention include members of the group consisting of C 2 -C 4 alcohols such such as ethanol and isopropanol, polyethylene glycol monolaurate, diethyl glycol monomethyl ether, polyethylene glycol-3-lauramide, dimethyl lauramide, dimethyl isosorbide, sorbitan trioleate, fatty acids, fatty acid esters having from about 10 to about 20 carbon atoms, monoglycerides or mixtures of fatty acid monoglycerides having a total monoester content of at least about 51% where the monoesters are those having 10 to 20 carbon atoms, and mixtures of mono-, di- and tri-glycerides of fatty acids. Although not limited thereto, suitable fatty acids include members of the group consisting of lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and palmitic acid. Permeation enhancers made from monoglycerides include members of the group consisting of glycerol monooleate, glycerol monolaurate and glycerol monolinoleate, for example. Although not limited thereto, examples of penetration enhancers that are useful in the methods of the invention include members of the group consisting of those described in US Patent Nos. 3,472,931, 3,527,864, 3,896,238, 3,903,256, 3,952,099, 3,989,816, 4,046,886, 4,130,643, 4,130,667, 4,299,826, 4,335,115, 4,343,798, 4,379. 454, 4,405,616, 4,746,515, 4,316,893, 4,405,616, 4,060,084, 4,379,454,
4,560,553, 4,863,952, 4,863,970, 4,879,275, 4,940,586, 4,960,771, 4,973,468, 5,066,648, 5,164,406, 5,227,169,
5,229,130, 5,238,933, 5,308,625, 4,326,566, 5,378,730, 5,420,106, 5,641,504, 5,716,638, 5,750,137, 5,785,991,
5,837,289, 5,834,468, 5,882,676, 5,912,009, 5,952,000 and 6,004,578, and in Idson J. Pharm. Sci. 64 (b6): 901-924 (1975), whose descriptions are incorporated herein by reference.

5.3 Active agents

The transdermal dosage form may comprise any pharmacologically active agent that is capable of inducing a desired biological or pharmacological effect that may include, but is not limited to, the effects of (1) affecting a living process; (2) have a prophylactic effect on an animal and prevent an unwanted effect, such as preventing an infection; (3) relieve a condition caused by a disease or a symptom thereof, such as p. ex . pain or swelling; and / or (4) alleviate, reduce or eliminate a disease, condition or symptom of the animal. The effect of the active agent can be local, such as producing an anesthetic effect, or it can be systemic or a combination of both. Although not limited to them, the general categories of active agents may in one embodiment include members of the group consisting of: opioids; ACE inhibitors (ACE = angiotensin conversion enzyme); adenohypophyseal hormones; blocking agents of adrenergic neurons; adrenocortical steroids; adrenocortical steroid biosynthesis inhibitors; alpha-adrenergic agonists; alpha-adrenergic antagonists; selective alpha-two-adrenergic agonists; androgens; anti-addictive agents; antiandrogens; anti-infectives, such as antibiotics, antimicrobials and antiviral agents; analgesics and combinations of analgesics; anorexics; anthelmintics; antiarthritics; anti-asthmatic agents; anticonvulsants, antidepressants; antidiabetic agents; antidiarrheals; antiemetic and prokinetic agents; antiepileptic agents; antiestrogens; antifungal agents; antihistamines; anti-inflammatory agents; antimigraine preparations; antimuscarinic agents; anti-nausents; antineoplastic; antiparasitic agents; antiparkinsonism drugs; antiplatelet agents; antiprogestins; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; antithyroid agents; cough suppressants; azaespirodecanodionas; sympathomimetics; xanthine derivatives; cardiovascular preparations, including members of the group consisting of potassium and calcium channel blockers, alpha blockers, beta blockers and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators, including cerebral, peripheral and general coronary; central nervous system stimulators; vasoconstrictors; cough and cold preparations, including decongestants; hormones, such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympathetic; psychostimulants; sedatives; tranquilizers; nicotine and acid addition salts thereof; benzodiazepines; barbiturates; benzothiadiacides; beta-adrenergic agonists; beta-adrenergic antagonists; selective beta-one-adrenergic antagonists; selective beta-two-adrenergic antagonists; bile salts; agents that affect the volume and composition of body fluids; butyrophenones; agents that affect calcification; catecholamines; cholinergic agonists; cholinesterase reactivators; dermatological agents; diphenylbutylpiperidines; ergot alkaloids; ganglionic blocking agents; hydantoins; agents for the control of gastric acidity and the treatment of peptic ulcers; hematopoietic agents; histamines; 5-hydroxytryptamine antagonists; drugs for the treatment of hyperlipiproteinemia; laxatives, methylxanthines; monoamine oxidase inhibitors; neuromuscular blocking agents; organic nitrates; pancreatic enzymes; phenothiazines; prostaglandins; retinoids; agents for spasticity and acute muscle spasms; succinimides; thioxanthines; thrombolytic agents; thyroid agents; tubular transport inhibitors of organic compounds; drugs that affect uterine motility; vitamins and similar substances, or a combination thereof.

The transdermal dosage form can comprise an active component that may include, but without limiting nature, to the members of the group consisting of acetate of flurogestone, hydroxyprogesterone, acetate hydroxyprogesterone, hydroxyprogesterone caproate, acetate Medroxyprogesterone, norethindrone, norethindrone acetate, norethisterone, noretinodrel, desogestrel, 3-keto-desogrestel, gestadene, levonorgestrel, estradiol, estradiol benzoate, valerate estradiol, estradiol cyprionate, estradiol decanoate, acetate of estradiol, ethinyl estradiol, estriol, estrone, mestranol, betamethasone, betamethasone acetate, cortisone, hydrocortisone, hydrocortisone acetate, corticosterone, fluocinolone acetonide, prednisolone, prednisone, triamcinolone, aldosterone, androsterone, testosterone, methyltestosterone, or a combination of same.

The transdermal dosage form may comprise an active component that may include, but is not limited to, members of the group consisting of: a) a corticosteroid, such as p. ex . cortisone, hydrocortisone, prednisolone, beclomethasone propionate, dexamethasone, betamethasone, flumetasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetate, clobetasol propionate, or the same substances, or the same substances; b) an analgesic anti-inflammatory agent, such as p. ex . acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, ibufenac, oxyphebutazone, phenylbutazone, ibuprofen, flurbiprofen, ketoprofen, salicylic acid, methyl salicylate, 1-menthetamine, sodium menthelic acid naproxen, fenbufen, or similar substances, or a combination thereof; c) a hypnotic sedative, such as p. ex . phenobarbital, amobarbital, cyclobarbital, loracepam, haloperidol, or similar substances, or a combination thereof; d) a tranquilizer, such as p. ex . fluphenazine, thioridazine, diazepam, fluracepam, chlorpromazine, or similar substances, or a combination thereof; e) an antihypertensive, such as p. ex . clonidine, clonidine hydrochloride, bopinidol, timolol, pindolol, propranolol, propranolol hydrochloride, bupranolol, indenolol, bucumolol, nifedipine, bunitrolol, or similar substances, or a combination thereof; f) a hypotensive diuretic, such as p. ex . bendroflumethiazide, polyamide, methylchlortiazide, trichlormethiazide, cyclopentiazide, benzylhydrochlorothiazide, hydrochlorothiazide, bumetanide, or similar substances, or a combination thereof; g) an antibiotic, such as p. ex . penicillin, tetracycline, oxytetracycline, methacycline, doxycycline, minocycline, fradiomycin sulfate, erythromycin, chloramphenicol, or similar substances, or a combination thereof; h) an anesthetic, such as p. ex . lidocaine, benzocaine, ethylaminobenzoate, or similar substances, or a combination thereof; i) another analgesic, such as p. ex . acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, naproxen and similar substances; j) an antipruritic agent, such as p. ex . bisabolol, chamomile oil, chamazulene, allantoin, D-panthenol, glycyrrhenic acid, a corticosteroid, an antihistamine and similar substances; k) an antimicrobial agent, such as p. ex . methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, nitrofurazone, nystatin, sulfacetamide, clotriamazole, or similar substances, or a combination thereof; l) an antifungal agent, such as p. ex . pentamicin, amphotericin B, pyrrolnitrin, clotrimazole, or similar substances, or a combination thereof; m) a vitamin, such as p. ex . vitamin A, ergocalciferol, cholecalciferol, octotriamine, butyric acid ester and riboflavin, or similar substances, or a combination thereof; n) an antiepileptic, such as p. ex . nitracepam, meprobamate, clonacepam, or similar substances, or a combination thereof; o) an antihistamine, such as p. ex . diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, or similar substances, or a combination thereof; p) an antitussive, such as p. ex . dextromethorphan, terbutaline, ephedrine, ephedrine hydrochloride, or similar substances, or a combination thereof; q) a sex hormone, such as p. ex . progesterone, estradiol, estriol, estrone, or similar substances, or a combination thereof; r) an antidepressant, such as p. ex . doxepine; s) a vasodilator, such as p. ex . nitroglycerin, isosorbide nitrate, nitroglycol, pentaerythritol tetranitrate, dipyridamole, or similar substances, or a combination thereof; t) another drug, such as p. ex . 5-fluorouracil, dihydroergotamine, desmopressin, digoxin, metoclopramide, domperidone, scopolamine, scopolamine hydrochloride, or similar substances, or a combination thereof.

The amount of active agent present in the Transdermal dosage form will depend in part on the active agent specific, of the type of device, of the materials used in the device, and of the period of time per space of which the Active agent will be contributed to the animal. The amount of active agent present in the transdermal dosage form, however, typically it goes from about 0.01 to a little or so 50 mg / cm2, preferably from about 0.05 to little more or less 15 mg / cm2, and more preferably since shortly plus or minus 0.05 to plus or minus 5.0 mg / cm2. Is from everything within the reach of a subject matter expert easily determine the amount of an active agent that is necessary for a particular indication.

5.4 Opioids

In the transdermal dosage form of The present invention can be used any Opioid. Although without be limited to these, useful Opioids include members of the group consisting of alfentanil, alylprodin, alphaprodin, anileridine, benzylmorphine, benzitramide, buprenorphine, butorphanol, clonitacene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dihydromorphone, dihydroisomorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafethyl butyrate, dipipanone, eptazocine, etoheptacin, ethylmethylthiambutene, ethylmorphine, etonitacene, etorphine, dihydroetorphine, fentanyl, heroin, hydrocodone, Hydromorphone, Hydromorphone, Hydroxipetidine, Isometadone, ketobemidone, levorphanol, levofenacylmorphan, lofentanyl, meperidine, meptacinol, methazocine, methadone, metopon, morphine, mirofin, narcein, nicomorphine, norlevorphanol, normetadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum, paregoric, pentazocine, pheadoxone, phendimetracine, phendimetrazone, pheromorphan, phenazocine,  phenoperidine, piminodine, piritramide, proheptacin, promedol, properidine, propoxyphene, propylhexedrine, sulfentanil, tilidine, tramdol, pharmaceutically acceptable salts thereof and mixtures of any two or more of them.

In certain embodiments, the Opioid is hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts of same, and mixtures of any two or more thereof. In a embodiment, the Opioid is oxycodone, hydrocodone, fentanyl, buprenorphine, or a pharmaceutically acceptable salt of same.

In one embodiment, especially for patches passive, an Opioid is in the form of a free base. For patches of the invention using iontophoresis to facilitate the penetration of the skin by an Opioid, however, a salt is preferred Pharmaceutically acceptable Opioid.

The analgesically effective amount of Opioid present in the transdermal dosage form will depend in part on the Specific opioid, of the type of device, of the materials that be used in the device, and of the period of time per space of the which Opioid will be contributed to the animal. The amount analgesically  Effective of an Opioid present in the transdermal dosage form, however, it typically ranges from about 0.01 to a little plus or minus 50 mg / cm2, preferably from a little or so 0.05 to about 15 mg / cm2, and more preferably from about 0.05 to about 5.0 mg / cm2. It is perfectly within the reach of an expert in the field to determine easily the analgesically effective amount of an Opioid that It will be necessary for a particular indication.

5.5 Adverse agent

The adverse agent can be any agent active pharmacist that at least partially reduces or blocks the less a biological effect of an active agent or create an effect unpleasant when absorbed into the bloodstream of an animal or a patient Although not limited to them, the Examples of adverse agents include group members who It consists of antagonists of any active agent. When in the Dosage form of the present invention is used as the active agent an opioid agonist, can be used as the adverse agent an opioid antagonist. Similarly, when in the Dosage form of the present invention is used as the active agent a benzodiazepine, can be used as the adverse agent a benzodiazepine antagonist. When in the Dosage form of the present invention is used as active agent a barbiturate, an adverse agent can be used as a barbiturate antagonist. When in the dosage form of the present invention an amphetamine is used as the active agent, an antagonist of the adverse agents can be used as amphetamines When the active agent is toxic when administered with a dosage higher than its normal therapeutic range, it is say, when there is a significant risk of overdose, then an antidote of the agent can be used as the adverse agent Toxic active

Although not limited to it, among benzodiazepine antagonists that can be used in quality of the adverse agent of the present invention is included the flumacenyl

Although not limited to them, enter barbiturate antagonists that can be used in Adverse agent quality of the present invention includes the amphetamines

Although not limited to them, the stimulant antagonists that can be used as quality of the adverse agent of the present invention include the benzodiazepines

In another embodiment of the present invention, the adverse agent is an agent that causes a physiological reaction unwanted, such as emesis. This type of adverse agent can be used with any kind of therapeutic agent, including a opioid, a benzodiazepine, a barbiturate or a stimulant. The examples of emetic agents that are suitable for use in Adverse agent quality in the present invention include a any drug that safely and effectively induces vomiting after the administration, including, but not limited to, the ipecac and apomorphine.

5.6 Opioid antagonist

Although not limited to them, the opioid antagonists that can be used in the methods and Transdermal dosage forms of the present invention include a the members of the group consisting of cyclazocine, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine, cyclazacin, levalorfan, pharmaceutically acceptable salts thereof, and mixtures thereof. In certain embodiments, the Antagonist is namelfeno, naloxone, naltrexone or a pharmaceutically salt acceptable of them. The Free Antagonist Base and Salt Antagonist may be based on the same antagonist or on different antagonists; and so for example, the Free Base Antagonist and Antagonist Salt can be naloxone and naloxone HCl, respectively.

In one embodiment, the Antagonist Salts useful include salts made from an acid and from the group basic nitrogen of a free base form of an antagonist. Although not limited to them, Sales examples Antagonists include members of the group consisting of salts sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, glubionate and pamoate (i.e. 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)).

Other Antagonist Salts include salts prepared from an Antagonist who has a functional group acid, such as a carboxylic acid or acid functional group sulfonic, and of a pharmaceutically inorganic or organic base acceptable. Although not limited to them, the bases suitable include members of the group consisting of alkali metal hydroxides such as sodium, potassium and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia, and organic amines such as mono-, di-, or trialkylamines unsubstituted or hydroxy-substituted; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris- (2-hydroxy alkyl lower amines), such as mono-, bis- or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine,  or tris- (hydroxymethyl) methylamine, N, N-di-alkyl lower-N- (hydroxy alkyl lower) -amines, such as N, N-dimethyl-N- (2-hydroxyethyl) amine,  or tri- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and substances Similar.

The amount of Antagonists present in the form Transdermal dosage and sufficient to inhibit the effect Euphoric of an active agent such as an Opioid depends in part of the specific Antagonists that are used in the device. Typically, the weight ratio of active agent such as a Opioid to the total number of Antagonists in the dosage form transdermal ranges from about 15: 1 to about 1: 5, and more preferably from about 12: 1 to approximately 4: 1. The combinations of illustrative antagonists They include the following:

naloxone HCl: free base of naltrexone, which in one embodiment has a weight ratio that is from about 5: 1 to about 1: 5, and in another realization is from about 1: 1 to about 1: 5;

naloxone free base: naltrexone HCl, which in one embodiment has a weight ratio that is from about 5: 1 to about 1: 5, and in another embodiment is from about 1: 5 to about 1: 1;

naloxone HCl: nalmefene free base, which in a embodiment has a weight ratio that is from about 5: 1 to about 1: 5, and in another embodiment it is from about 1: 1 to about 1: 5; Y

naltrexone HCl: nalmefene free base, which in one embodiment has a weight ratio that is from about 5: 1 to about 1: 5, and in another realization is from about 1: 1 to about 1: 5.

In one embodiment, the Opioid is fentanyl. The combinations of fentanyl: Illustrative antagonists include the following:

fentanyl: naloxone HCl: naltrexone free base, which in one embodiment has a weight ratio of the combination of fentanyl: Antagonist (total amount) that is from about 10: 1 to about 1: 5, and in another embodiment is from about 10: 1 to about 4: 1;

fentanyl: naloxone free base: naltrexone HCl, which in one embodiment has a weight ratio of fentanyl: Antagonist (total amount) that is from approximately 10: 1 to about 1: 5, and in another embodiment it is from about 10: 1 to about 4: 1;

fentanyl: naloxone HCl: nalmefene free base, which in one embodiment has a weight ratio of fentanyl: Antagonist (total amount) that is from approximately 15: 1 to about 1: 5, and in another embodiment it is from about 12: 1 to about 4: 1; Y

fentanyl: naltrexone HCl: free base nalmefene, which in one embodiment has a weight ratio of fentanyl: Antagonist (total amount) that is from approximately 15: 1 to about 1: 5, and in another embodiment it is from about 12: 1 to about 4: 1.

A subject matter expert can easily determine the amount of antagonists needed for a particular indication.

5.7 Methods to treat or prevent pain

According to an embodiment of the invention, the form Transdermal dosage of the invention can be used for administer to an animal, and preferably to a mammal, and more preferably to a human, an analgesically effective amount of an active agent, such as an Opioid, for treatment or pain prevention The transdermal dosage form can be used to treat or prevent acute or chronic pain. Although without be limited to such applications, the dosage form Transdermal can be used for example to treat or prevent cancer pain, central pain, labor pain, pain of myocardial infarction, pancreatic pain, colic pain, postoperative pain, headache pain, muscle pain, bone pain and pain associated with intensive care.

According to the methods of the invention, the form Transdermal dosage is brought into contact with the skin of the animal, and an active agent such as an Opioid is released by the transdermal dosage form and becomes absorbed through the animal skin Once absorbed into the animal, an active agent just as an Opioid is contributed in an analgesic amount effective. The transdermal dosage form can provide a sustained and continuous contribution of an analgesically effective amount of an active agent. In one embodiment, the dosage form Transdermal of the invention maintains a level of an active agent such as an Opioid in the animal's bloodstream between about 0.1 and about 100 nanograms of agent active per milliliter of blood plasma for a period of time of time from about 16 hours to about 7 days, in another embodiment from about 16 hours to about 72 hours, and in a further embodiment, of at least about 24 hours. In another embodiment, the transdermal dosage form of the invention maintains a level of an active agent such as a Opioid in the animal's bloodstream enough to achieve an analgesic effect, and consequently to treat or prevent the pain for a period of time between approximately 15 minutes and approximately 7 days, in another embodiment between about 1 hour and about 72 hours, and in yet another realization, at least about 24 hours.

The transdermal dosage forms of invention are useful for treating or preventing pain in an animal to basis of putting the skin of an animal that needs it in contact with a transdermal dosage form of the invention by space for a sufficient amount of time to treat or prevent pain, and for example over a period of time of approximately 10 minutes to approximately 72 hours. In a embodiment, the amount of time is about 30 minutes about 24 hours

5.8 Kits (Kits = sets of materials and Utensils)

The present invention is also directed to a kit comprising at least one dosage form of the invention. In one embodiment, the dosage form is present in a container, such as p. ex . A bottle or a box. In another embodiment, the kit further comprises a set of instructions that indicate how to use the dosage form to treat a patient, e.g. ex . Regarding pain. In one embodiment, the instructions may be a printed label attached to the package or printed on it. In another embodiment, the instructions may comprise a printed sheet inserted in the package or in the packing containing the package. The instructions may also indicate that the dosage form and / or its use are designed to reduce abuse or misuse of the dosage form or deviation from its correct form of use.

The following examples are given to help understand the invention, and naturally they should not be interpreted as something that specifically limits the invention that Here it is described and claimed. They should be considered to remain inside of the scope of the invention presented here such variations of the invention, including the replacement of its parts members for any equivalents that are currently know or be developed later, which would remain perfectly available to experts in the field, and formulation changes or small design changes experimental.

6. Examples

The following examples are prophetic examples. which are believed to be functional either as indicated or with minor modifications like those that would be known for a skilled. The examples serve to illustrate the scope of the present invention, and not to limit it.

Example one

A transdermal dosage form was prepared according to Figure 3A, in which the first layer of adhesive comprised 15 mg / cm 2 of fentanyl free base in adhesive. The second layer of adhesive comprised 15 mg / cm2 of nalmefene HCl in adhesive. Several 2 cm 2 portions of the device were punched out, the protective coating was removed, and the portions were immobilized and placed in test vessels. The amount of fentanyl and nalmefene HCl free base that was likely to be removed from the device (and was therefore potentially available for abuse) and in some cases is contained within the transdermal delivery device was determined by extraction using the following solvents : phosphate buffered saline ("PBS"), alcohol / water mixture and ethyl ether. Aliquots of 15 ml of solvent were used in each extraction. The PBS solution was prepared by combining equal amounts of a 0.1M phosphate buffer (pH 6.5) and a 0.5M chloride solution.
sodium The alcohol / water mixture was prepared by mixing 75 parts of absolute ethanol with 25 parts of water.

The vials with the test samples were placed on a laboratory shaker and stirred at 20 rpm. Were several 1000 µl portions removed at 5 minute intervals, and they were analyzed using liquid chromatography. Using liquid chromatography an analysis was performed for determination of both the fentanyl free base and the nalmefene HCl.

The results of the analysis for determination of the free base of fentanyl are indicated in the Table 1, and the results of the analysis for the determination of nalmefene HCl are indicated in Table 2. Figure 4 shows the amounts (micrograms / minute) of fentanyl free base and of nalmefene HCl extracted from the device using PBS, the mixture of alcohol / water and diethyl ether, respectively.

TABLE 1

one

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TABLE 2

2

Example 2

A transdermal dosage form was prepared according to Figure 3A, where the first layer of adhesive comprised 15 mg / cm2 of fentanyl free base in adhesive. The second layer of adhesive comprised approximately equal amounts of Naltrexone and nalmefene HCl in adhesive, with a total load of 15 mg / cm2. Several 2 cm2 portions of the device, the protective coating was removed, and the portions were immobilized and placed in containers of test. The amount of fentanyl free base, nalmefene HCl and naltrexone that was likely to be removed from the device (and therefore it was potentially available for abuse) and in some cases it is contained within the contribution system transdermal was determined by extraction using the following solvents: PBS, alcohol / water and ether mixture diethyl Aliquots of 15 ml of solvent The PBS solution was prepared by combining amounts Equals of a 0.1M phosphate buffer (pH 6.5) and a 0.5M solution of sodium chloride. The alcohol / water mixture was prepared mixing 75 parts of absolute ethanol with 25 parts of water.

The vials with the test samples were placed on a laboratory shaker and stirred at 20 rpm. Were several 1000 µl portions removed at 5 minute intervals, and they were analyzed using liquid chromatography. Using liquid chromatography an analysis was performed for determination of the free base of fentanyl, nalmefene HCl and Naltrexone

The results of the analysis for determination of the free base of fentanyl, nalmefene HCl and Naltrexone are indicated in Tables 3, 4 and 5, respectively. Figure 5 shows the quantities (micrograms / minute) of free base of fentanyl, nalmefene HCl and naltrexone extracted from the device using PBS, the mixture of alcohol / water and diethyl ether, respectively.

TABLE 3

3

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TABLE 4

4

TABLE 5

5

Example 3

Table 6 indicates the data obtained by having after 30 minutes for patches tested as indicated in Examples 1 and 2.

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TABLE 6

6

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The relationships indicated are the amount of extracted fentanyl divided by the total amount of antagonist extracted.

As shown in Table 6, the extraction of an illustrative transdermal dosage form of the invention gives as a result a mixture of an Opioid and an Antagonist. The ratio of Opioid extracted to Antagonist extracted total in a patch that has an Opioid, an Antagonist Free Base and a Salt Antagonist is lower than that of a transdermal device that It has only one Opioid and one Antagonist Salt. Due to the fact that with the extraction of the transdermal dosage form illustrative a lower ratio of Opioid extracted to Antagonists extracted with respect to a device containing Only one Opioid and one Antagonist Salt, the dosage forms transdermal of the invention are advantageous in that the they are useful to deter abuse or prevent abuse of a Pharmaceutical agent such as an Opioid.

Example 4

Fentanyl free base (5.0 g) is added to ethanol (25 g) with mixture. Naloxone HCl (2.5 g) is added to water (50 g) and propylene glycol (10 g) with mixing until dissolved. To Naloxone HCl solution is added naltrexone (2.5 g) in ethanol (10 g) The resulting solution is combined with the solution of fentanyl to form the reservoir vehicle. For the adjustment of the viscosity hydroxypropylcellulose is added in a percentage of a 0.2-5.0% of the total weight of the solution. A membrane Intermediate barrier (COTRAN 9702, 3M Company) is coated with a skin contact adhesive (Solutia 737), and the adhesive is protected with a removable non-stick coating (SCOTCHPAK 1022, 3M Company). A lining film (COTRAN 9701, 3M Company) It is laminated with the membrane with a partial opening to allow vertical filling with reservoir vehicle. After having done reservoir vehicle filling up to a load of 5.0 mg / cm2 of fentanyl, the opening is laminated in order to obtain a reservoir-type transdermal dosage form heat seal. The reservoir contains a ratio of 1 part of fentanyl to 1 part of total antagonist, being the ratio of 1 part naloxone HCl antagonists to 1 part naltrexone. The Transdermal dosage form is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring at the same time.

Example 5

Fentanyl free base (5.0 g) is added to ethanol (20 g) with mixing. Naloxone HCl (0.25 g) is added to water
(44 g) and propylene glycol (5 g) with mixing until dissolved. To the solution of naloxone HCl is added naltrexone (0.25 g) in ethanol (20 g). The resulting solution is combined with the fentanyl solution to form the reservoir vehicle. To adjust the viscosity, hydroxypropylcellulose is added in a percentage of 0.2-5.0% of the total solution weight. An intermediate barrier membrane (Medifilm 390, Mylan) is coated with a skin contact adhesive (National Starch 387-2051), and the adhesive is protected with a removable non-stick coating (SCOTCHPAK 1022, 3M Company). A liner film (SCOTCHPAK 9735, 3M Company) is laminated with the membrane with a partial opening to allow vertical filling with a reservoir vehicle. After filling with a reservoir vehicle to a load of 5.0 mg / cm2 of fentanyl, the opening is laminated to obtain a thermosealed reservoir-type transdermal dosage form. The reservoir contains a ratio of 10 parts of fentanyl to 1 part of Total Antagonist, the ratio of antagonists being 1 part of naloxone HCl to 1 part of naltrexone. The transdermal dosage form is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring it at the same time.

Example 6

Fentanyl free base (10 g) is added to ethanol (20 g) with mixture. Naloxone HCl (8 g) is added to water (37.5 g) and propylene glycol (7.5 g) with mixing until dissolved. TO Naloxone HCl solution is added naltrexone (2 g) in ethanol (15 g). The resulting solution is combined with the solution of fentanyl to form the reservoir vehicle. For the adjustment of the viscosity hydroxypropylcellulose is added in a percentage of a 0.2-5.0% of the total solution weight. A membrane Intermediate barrier (COTRAN 9726, 3M Company) is coated with a skin contact adhesive (Solutia 737), and the adhesive is protected with a removable non-stick coating (SCOTCHPAK 1022, 3M Company). A lining film (SCOTCHPAK 9735, 3M Company) is laminated with the membrane with a partial opening for allow vertical filling with reservoir vehicle. Behind the filling with reservoir vehicle up to a load of 2.5 mg / cm2 of fentanyl, the opening is laminated to obtain a Thermosealed reservoir type transdermal dosage form. He reservoir contains a ratio of 1 part fentanyl to 1 part Total antagonist, being the ratio of 4 antagonists parts of naloxone HCl to 1 part of naltrexone. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 7

Fentanyl free base (10 g) is added to ethanol (25 g) with mixing. Naloxone HCl (2 g) is added to water
(25 g) and propylene glycol (5 g) with mixing until dissolved. To the solution of naloxone HCl is added naltrexone (8 g) in ethanol (25 g). The resulting solution is combined with the fentanyl solution to form the reservoir vehicle. To adjust the viscosity, hydroxypropylcellulose is added in a percentage of 0.2-5.0% of the total solution weight. An intermediate barrier membrane (COTRAN 9726, 3M Company) is coated with a skin contact adhesive (Solutia 737), and the adhesive is protected with a removable non-stick coating (SCOTCHPAK 1022, 3M Company). A liner film (SCOTCHPAK 9735, 3M Company) is laminated with the membrane with a partial opening to allow vertical filling with a reservoir vehicle. After filling with a reservoir vehicle to a load of 2.5 mg / cm 2 of fentanyl, the opening is laminated to obtain a thermosealed reservoir-type transdermal dosage form. The reservoir contains a ratio of 1 part fentanyl to 1 part total antagonist, the ratio of antagonists being 1 part naloxone HCl to 4 parts naltrexone. The transdermal dosage form is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring it at the same time.

Example 8

Fentanyl free base (5.0 g) is added to ethanol (15 g) with mixture. Naloxone HCl (0.9 g) is added to water (59 g) and propylene glycol (10 g) with mixing until dissolved. To Naloxone HCl solution is added naltrexone (0.1 g) in ethanol (10 g) The resulting solution is combined with the solution of fentanyl to form the reservoir vehicle. For the adjustment of the viscosity hydroxypropylcellulose is added in a percentage of a 0.2-5.0% of the total solution weight. A membrane Intermediate barrier (COTRAN 9726, 3M Company) is coated with a skin contact adhesive (Solutia 737), and the adhesive is protected with a removable non-stick coating (SCOTCHPAK 1022, 3M Company). After filling with reservoir vehicle until a 5.0 mg / cm2 load of fentanyl, a liner film (SCOTCHPAK 9735, 3M Company) is laminated with the membrane so obtain a reservoir-type transdermal dosage form heat seal. The reservoir contains a ratio of 5 parts of fentanyl to 1 part of total antagonist, being the ratio of 9 part naloxone HCl antagonists to 1 part naltrexone. The transdermal dosage form is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring at the same time.

Example 9

Fentanyl free base (7.5 g) is added to ethanol (12.5 g) with mixing until dissolved. Naloxone HCl (0.25 g) is added to water (68 g) and propylene glycol (3 g) with mixing until dissolution Naltrexone is added to the naloxone HCl solution (1.25 g) in ethanol (7.5 g). The resulting solution is combined with the fentanyl solution to form the reservoir vehicle. To adjust the viscosity, hydroxypropylcellulose is added in a percentage of 0.2-5.0% of the weight of the solution total. An intermediate barrier membrane (COTRAN 9726, 3M Company) It is coated with a skin contact adhesive (Solutia 737),  and the adhesive is protected with a non-stick coating removable (SCOTCHPAK 1022, 3M Company). After filling with vehicle reservoir up to a load of 5.0 mg / cm2 of fentanyl, a Lining film (SCOTCHPAK 9735, 3M Company) is laminated with the membrane to obtain a transdermal dosage form heat sealed reservoir. The reservoir contains a ratio of 5 parts of fentanyl to 1 part of total antagonist, being the ratio of 1 part naloxone HCl antagonists to 5 parts of Naltrexone The transdermal dosage form is useful for treating or prevent pain in an animal, while preventing abuse Opioid or deterring at the same time.

Example 10

Free base of fentanyl (5.0 g) and lauric acid (2.5 g) are added to ethanol (15 g) with mixing until dissolution. Naloxone HCl (2.5 g) is added to water (45 g) with mixing Until dissolution. To the naloxone HCl solution is added Naltrexone (2.5 g) in ethanol (15 g). The resulting solution is combined with the fentanyl solution to form the vehicle reservoir For viscosity adjustment is added hydroxypropylcellulose in a percentage of a 0.2-5.0% of the total solution weight. A membrane Intermediate barrier (COTRAN 9702, 3M Company) is coated with a skin contact adhesive (Solutia 737), and the adhesive is protected with a removable non-stick coating (SCOTCHPAK 1022, 3M Company). After filling with reservoir vehicle until a 5.0 mg / cm2 load of fentanyl, a liner film (SCOTCHPAK 9735, 3M Company) is laminated with the membrane so obtain a reservoir-type transdermal dosage form heat seal. The reservoir contains a ratio of 1 part of fentanyl to 1 part of total antagonist, being the ratio of 1 part naloxone HCl antagonists to 1 part naltrexone. The Transdermal dosage form is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring at the same time.

Example eleven

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. Naloxone free base (5 g) is dissolved in methanol (25 g) and naltrexone HCl (5 g) is dissolved in water (25 g), and the two solutions are combined and added to the solution of fentanyl A solvent-based pressure sensitive adhesive (Dow Silicones # 7-4400) is added to the solution in sufficient quantity to obtain a combined solution that contains, by weight of solids, 90% adhesive solids, 5% of fentanyl, 2.5% of naloxone free base and 2.5% of Naltrexone HCl. The mixture of fentanyl and adhesive is poured onto a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. A covering lining tape made from film of Polyethylene (SCOTCHPAK 9732, 3M Company) is hot rolled being applied to the upper surface of the adhesive layer. The resulting transdermal dosage form contains a ratio of 1 part of fentanyl to 1 part of total antagonist, being the ratio of 1 part naloxone free base antagonists to 1 part of naltrexone HCl. The transdermal dosage form is useful to treat or prevent pain in an animal, preventing it Opioid abuse time or deterring at the same time same.

Example 12

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. Naloxone free base (0.5 g) is dissolved in methanol (25 g) and naltrexone HCl (0.5 g) is dissolved in water (25 g), and the two solutions are combined and added to the fentanyl solution A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4400) is added to the solution in sufficient quantity to obtain a combined solution containing, by weight of solids, 94% adhesive solids, a 5% fentanyl, 0.25% naloxone free base and 0.25% Naltrexone HCl. The mixture of fentanyl and adhesive is poured onto a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. A covering lining tape made from film Polyethylene (SCOTCHPAK 9732, 3M Company) is hot rolled being applied to the upper surface of the adhesive layer. The resulting transdermal dosage form contains a ratio of 10 parts of fentanyl to 1 part of total antagonist, being the ratio of 1 part naloxone free base antagonists to 1 part of naltrexone HCl. The transdermal dosage form is useful to treat or prevent pain in an animal, preventing it Opioid abuse time or deterring at the same time same.

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Example 13

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. Naloxone free base (8 g) is dissolved in methanol (45 g) and naltrexone HCl (2 g) is dissolved in water (25 g), and the two solutions are combined and added to the solution of fentanyl A solvent-based pressure sensitive adhesive (Solutia 737) is added to the solution in sufficient quantity to obtain a combined solution containing, by weight of solids, 90% of adhesive solids, 5% fentanyl, 4% free base naloxone and 1% naltrexone HCl. The mixture of fentanyl and adhesive is poured onto a nonstick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. The layer of coating contains a fentanyl free base charge of 15 mg / cm2. A covering lining tape made from polyethylene film (SCOTCHPAK 9732, 3M Company) is laminated in hot being applied to the top surface of the layer of adhesive. The resulting transdermal dosage form contains a ratio of 1 part fentanyl to 1 part total antagonist, the 4-part antagonist ratio being free base of naloxone to 1 part of naltrexone HCl. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 14

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. Naloxone free base (2 g) is dissolved in methanol (25 g) and naltrexone HCl (8 g) is dissolved in water (45 g), and the two solutions are combined and added to the solution of fentanyl A solvent-based pressure sensitive adhesive (Solutia 737) is added to the solution in sufficient quantity to obtain a combined solution containing, by weight of solids, 90% of Adhesive solids, 5% fentanyl, 1% free base naloxone and 4% naltrexone HCl. The mixture of fentanyl and adhesive is poured onto a nonstick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. The layer of coating contains a fentanyl free base charge of 15 mg / cm2. A covering lining tape made of film Polyethylene (SCOTCHPAK 9732, 3M Company) is hot rolled being applied to the upper surface of the adhesive layer. The resulting transdermal dosage form contains a ratio of 1 part of fentanyl to 1 part of total antagonist, being the ratio of 1 part naloxone free base antagonists to 4 parts of naltrexone HCl. The transdermal dosage form is useful to treat or prevent pain in an animal, preventing it Opioid abuse time or deterring at the same time same.

Example fifteen

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. Naloxone free base (1.8 g) is dissolved in methanol (20 g) and naltrexone HCl (0.2 g) is dissolved in water (15 g), and the two solutions are combined and added to the fentanyl solution A pressure sensitive adhesive based on Solvent (Solutia 737) is added to the solution in quantity enough to get a combined solution that contains, in weight of solids, 94% adhesive solids, 5% fentanyl, 0.9% naloxone free base and 0.1% naltrexone HCl. The mixture of fentanyl and adhesive is poured onto a coating non-stick (SCOTCHPAK 1022, 3M Company) and dried to remove The solvents The coating layer contains a load of 15 mg / cm2 fentanyl free base. A lining tape covering made of polyethylene film (SCOTCHPAK 9732, 3M Company) is hot rolled being applied to the surface upper layer of adhesive. The transdermal dosage form resulting contains a ratio of 5 parts fentanyl to 1 part Total antagonist, being the ratio of antagonists of 9 parts Naloxone free base to 1 part of naltrexone HCl. The shape Transdermal dosage is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring at the same time.

Example 16

Fentanyl free base (7.5 g) is added to methanol (90 g) with mixture. Naloxone free base (0.25 g) is dissolved in methanol (20 g) and naltrexone HCl (1.25 g) is dissolved in water (20 g), and the two solutions are combined and added to the fentanyl solution A pressure sensitive adhesive based on Solvent (Solutia 737) is added to the solution in quantity enough to get a combined solution that contains, in solids weight, 91% adhesive solids, 7.5% of fentanyl, 0.25% of naloxone free base and 1.25% of Naltrexone HCl. The mixture of fentanyl and adhesive is poured onto a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. A covering lining tape made of polyethylene film (SCOTCHPAK 9732, 3M Company) is hot rolled being applied to the upper surface of the adhesive layer. The shape resulting transdermal dosage contains a 5 part ratio from fentanyl to 1 part of total antagonist, being the ratio of 1 part naloxone free base antagonists to 5 parts of Naltrexone HCl. The transdermal dosage form is useful for treating or prevent pain in an animal, while preventing Opioid abuse or deterring at the same time.

Example 17

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to obtain a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

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Naloxone HCl (5 g) is dissolved in water (25 g) and nalmefene free base (5 g) is dissolved in methanol (25 g), and the 2 solutions are combined and added to a mixture of adhesive as the one described above, to form a naloxone mixture HCl-nalmefene-adhesive containing, by weight of solids, 90% adhesive solids, 5% base free of nalmefene and 5% naloxone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. The naloxone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naloxone mixture HCl-nalmefene-adhesive contains a combined naloxone HCl and nalmefene load of 15 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form It contains a ratio of 1 part of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 1 part of naloxone HCl to 1 part of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 18

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naloxone HCl (0.5 g) is dissolved in water (20 g) and nalmefene free base (0.5 g) is dissolved in methanol (20 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a naloxone mixture HCl-nalmefene-adhesive containing, by weight of solids, 99% adhesive solids, 0.5% base free of nalmefene and 0.5% naloxone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer it contains a fentanyl free base charge of 13.5 mg / cm2. Naloxone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naloxone mixture HCl-nalmefene-adhesive contains a combined naloxone HCl and nalmefene load of 1.5 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form contains a ratio of 10 parts of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 1 part of naloxone HCl to 1 part of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 19

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to obtain a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naltrexone HCl (5 g) is dissolved in water (25 g) and nalmefene free base (5 g) is dissolved in methanol (25 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a mixture of naltrexone HCl-nalmefene-adhesive containing, by weight of solids, 90% adhesive solids, a 5% nalmefene free base and 5% naltrexone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. The naltrexone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naltrexone mixture HCl-nalmefene-adhesive contains a combined naltrexone HCl and nalmefene load of 15 mg / cm2. The barrier membrane is then laminated with the non-stick coating, whereby the layer it contains fentanyl is separated from the layer containing Antagonist by the barrier membrane The coating covered with 2 layers resulting is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The shape Transdermal dosage contains a ratio of 1 part of fentanyl to 1 part of total antagonist, being the ratio of antagonists of 1 part of naltrexone HCl to 1 part of nalmefene. The transdermal dosage form is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring at the same time.

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Example twenty

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naltrexone HCl (0.5 g) is dissolved in water (20 g) and nalmefene free base (0.5 g) is dissolved in methanol (20 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a mixture of naltrexone HCl-nalmefene-adhesive containing, by weight of solids, 99% adhesive solids, a 0.5% nalmefene free base and 0.5% naltrexone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer it contains a fentanyl free base charge of 13.5 mg / cm2. Naltrexone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naltrexone mixture HCl-nalmefene-adhesive contains a combined naltrexone HCl and nalmefene load of 1.5 mg / cm2. The barrier membrane is then laminated with the non-stick coating, whereby the layer it contains fentanyl is separated from the layer containing Antagonist by the barrier membrane The coating covered with 2 layers resulting is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The shape Transdermal dosage contains a ratio of 10 parts of fentanyl to 1 part of total antagonist, being the ratio of antagonists of 1 part of naltrexone HCl to 1 part of nalmefene. The transdermal dosage form is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring at the same time.

Example twenty-one

Fentanyl free base (5.0 g) is added to methanol (90 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naloxone HCl (0.9 g) is dissolved in water (20 g) and nalmefene free base (0.1 g) is dissolved in methanol (20 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a naloxone mixture HCl-nalmefene-adhesive containing, by weight of solids, 99% adhesive solids, 0.9% base free of nalmefene and 0.1% of naloxone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer it contains a fentanyl free base charge of 12 mg / cm2. The naloxone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naloxone mixture HCl-nalmefene-adhesive contains a combined naloxone HCl and nalmefene load of 3 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form It contains a ratio of 5 parts of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 9 parts of naloxone HCl to 1 part of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 22

Fentanyl free base (7.5 g) is added to methanol (75 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naloxone HCl (0.25 g) is dissolved in water (20 g) and nalmefene free base (1.25 g) is dissolved in methanol (20 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a naloxone mixture HCl-nalmefene-adhesive containing, by weight of solids, 97.75% adhesive solids, 0.375% of nalmefene free base and 1,875% naloxone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. The naloxone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naloxone mixture HCl-nalmefene-adhesive contains a combined naloxone HCl and nalmefene load of 3 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form It contains a ratio of 5 parts of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 1 part of naloxone HCl to 5 parts of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 2. 3

Fentanyl free base (10 g) is added to methanol (90 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naltrexone HCl (0.2 g) is dissolved in water (20 g) and nalmefene free base (1.8 g) is dissolved in methanol (20 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a mixture of naltrexone HCl-nalmefene-adhesive containing, by weight of solids, 98% adhesive solids, a 1.8% free base of nalmefene and 0.2% of naltrexone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. The naltrexone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naltrexone mixture HCl-nalmefene-adhesive contains a naltrexone HCl and nalmefene loading combined of 3 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form It contains a ratio of 5 parts of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 1 part of Naltrexone HCl to 9 parts of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 24

Fentanyl free base (7.5 g) is added to methanol (75 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naloxone HCl (0.9 g) is dissolved in water (20 g) and nalmefene free base (0.1 g) is dissolved in methanol (20 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a naloxone mixture HCl-nalmefene-adhesive containing, by weight of solids, 99% adhesive solids, 0.1% base free of nalmefene and 0.9% naloxone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer It contains a fentanyl free base charge of 15 mg / cm2. The naloxone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naloxone mixture HCl-nalmefene-adhesive contains a combined naloxone HCl and nalmefene load of 1.0 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form it contains a ratio of 15 parts of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 9 parts of naloxone HCl to 1 part of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or discouraging the Same time of it.

Example 25

Fentanyl free base (21 g) is added to methanol (150 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 90% adhesive solids and 10% fentanyl.

Naltrexone HCl (2 g) is dissolved in water (20 g) and nalmefene free base (5 g) is dissolved in methanol (25 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a mixture of naltrexone HCl-nalmefene-adhesive containing, by weight of solids, 95.975% solids of adhesive, 2,875% of nalmefene free base and 1,15% of Naltrexone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer it contains a fentanyl free base charge of 12 mg / cm2. The naltrexone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naltrexone mixture HCl-nalmefene-adhesive contains a combined naltrexone HCl and nalmefene load of 4 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form It contains a ratio of 3 parts of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 1 part of Naltrexone HCl to 2.5 parts of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 26

Fentanyl free base (6 g) is added to methanol (65 g) with mixture. A pressure sensitive adhesive based on Solvent (Dow Silicones # 7-4402) is added to the solution in sufficient quantity to produce a mixture of combined fentanyl and adhesive containing, by weight of solids, a 88% adhesive solids and 12% fentanyl.

Naltrexone HCl (0.33 g) is dissolved in water (15 g) and nalmefene free base (0.67 g) is dissolved in methanol (20 g), and the 2 solutions are combined and added to a mixture of adhesive as described above, to form a mixture of naltrexone HCl-nalmefene-adhesive containing, by weight of solids, 97% adhesive solids, a 2% free base of nalmefene and 1% of naltrexone HCl.

The mixture of fentanyl and adhesive is poured on a non-stick coating (SCOTCHPAK 1022, 3M Company) and dried to remove solvents. Coating layer it contains a fentanyl free base charge of 12 mg / cm2. The naltrexone mixture HCl-nalmefene-adhesive is poured on a barrier membrane (SCOTCHPAK 1006, 3M Company) and dried to remove solvents. The coating made from the naltrexone mixture HCl-nalmefene-adhesive contains a combined naltrexone HCl and nalmefene load of 2 mg / cm2. The Barrier membrane is then laminated with the coating non-stick, whereby the layer containing fentanyl is separated from the layer containing Antagonist by the membrane of barrier. The resulting 2-layer coated coating is laminated with a polyester film cover (SCOTCHPAK 9732, supplied by the 3M Company). The transdermal dosage form It contains a ratio of 6 parts of fentanyl to 1 part of Total antagonist, being the ratio of antagonists of 1 part of Naltrexone HCl to 2 parts of nalmefene. The dosage form Transdermal is useful for treating or preventing pain in an animal, while preventing abuse of the Opioid or deterring Same time of it.

Example 27

A transdermal device of 15 is prepared mg / cm2 of fentanyl according to Examples 17-26. In this example, however, the layer of Antagonist-adhesive is prepared and incorporated into the Dosage form of contribution by transfer in the form of two independent but contiguous layers, which are a first layer that contains a mixture of naloxone HCl-adhesive, with a naloxone HCl load of 7.5 mg / cm2, and a second layer which contains a mixture of nalmefene-adhesive, with a nalmefene load of 7.5 mg / cm2. The dosage forms Transdermal are useful for treating or preventing pain in a animal, while preventing abuse of the Opioid or deterring at the same time.

The present invention should not be limited in as to its scope for the specific realizations here have described Certainly, in light of the above description and of the accompanying figures will be evident to experts in the subject various modifications of the invention in addition to those  Here they have been described. It is intended that such modifications remain within the scope of the appended claims.

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References cited in the description

This list of references cited by the applicant is provided only as information for the reader and is not part of the European patent document. Although there has been great care in compiling the references, the possibility of errors or omissions cannot be excluded, and the EPO disclaims all responsibility in this regard .

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Claims (35)

1. Transdermal dosage form that understands: an active agent or a pharmaceutically salt acceptable thereof; an antagonist in the form of a free base; Y an antagonist in the form of a salt pharmaceutically acceptable. 2. The transdermal dosage form of claim 1, wherein the antagonist that is in the form of a free base is present in an amount that is sufficient to inhibit at least one biological effect of the active agent or salt pharmaceutically acceptable thereof. 3. The transdermal dosage form of claim 1, wherein the pharmaceutically acceptable salt of the antagonist is present in an amount that is sufficient to inhibit at least one biological effect of the active agent or salt pharmaceutically acceptable thereof. 4. The transdermal dosage form of claim 1, wherein both the antagonist that is in the form of a free base as the pharmaceutically acceptable salt of antagonist are present in an amount that is sufficient to inhibit at least one biological effect of the active agent or salt acceptable of it. 5. The transdermal dosage form of claim 1, wherein the pharmaceutically acceptable salt of the antagonist and the antagonist that is in the form of a free base They are based on the same antagonist. 6. The transdermal dosage form of claim 1, wherein the amount of the active agent or a salt pharmaceutically acceptable thereof is about 0.1 to approximately 500 mg and the weight ratio of the active agent or of the pharmaceutically acceptable salt thereof to the total amount of antagonist that is in the form of a free base and salt pharmaceutically acceptable of an antagonist is approximately 15: 1 to about 1: 5. 7. The transdermal dosage form of claim 1, wherein the amount of the active agent or a salt pharmaceutically acceptable thereof is about 0.1 to approximately 500 mg and the weight ratio of the active agent or of the pharmaceutically acceptable salt thereof to the total amount of antagonist in the form of a free base and pharmaceutically salt acceptable of an antagonist is about 12: 1 to approximately 4: 1. 8. The transdermal dosage form of claim 1, wherein the transdermal dosage form comprises a reservoir comprising the active agent or a salt pharmaceutically acceptable thereof, to the antagonist in the form of a free base and pharmaceutically acceptable salt of a antagonist. 9. The transdermal dosage form of claim 1, wherein the transdermal dosage form is a Polymer matrix type transdermal dosage form. 10. The transdermal dosage form of claim 1, wherein the transdermal dosage form is a Transdermal dosage form in drug type adhesive. 11. The transdermal dosage form of claim 1, wherein the active agent is an opioid or a salt pharmaceutically acceptable thereof; and both the antagonist in form of a free base as the pharmaceutically acceptable salt of an antagonist are opioid antagonists. 12. The transdermal dosage form of claim 11, wherein the opioid antagonist in the form of a free base is present in an amount that is sufficient to inhibit the euphoric effect of opioid or salt pharmaceutically acceptable thereof. 13. The transdermal dosage form of claim 11, wherein the pharmaceutically acceptable salt of the opioid antagonist is present in an amount that is sufficient to inhibit the euphoric effect of opioid or salt pharmaceutically acceptable thereof. 14. The transdermal dosage form of claim 11, wherein both the opioid antagonist in the form of a free base as the pharmaceutically acceptable salt of opioid antagonist are present in an amount that is enough to inhibit the euphoric effect of the opioid or the pharmaceutically acceptable salt thereof. 15. The transdermal dosage form of claim 11, wherein the pharmaceutically acceptable salt of the opioid antagonist and the opioid antagonist that is in the form of A free base are based on the same opioid antagonist.

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16. The transdermal dosage form of claim 11, wherein the amount of the opioid or a salt pharmaceutically acceptable thereof is about 0.1 to approximately 500 mg and the weight ratio of the opioid or the pharmaceutically acceptable salt thereof at the total amount of opioid antagonist in the form of free base and salt pharmaceutically acceptable of an opioid antagonist is of about 15: 1 to about 1: 5. 17. The transdermal dosage form of claim 11, wherein the amount of the opioid or a salt pharmaceutically acceptable thereof is about 0.1 to approximately 500 mg and the weight ratio of the opioid or the pharmaceutically acceptable salt thereof at the total amount of opioid antagonist in the form of a free base and salt pharmaceutically acceptable of an opioid antagonist is of about 12: 1 to about 4: 1. 18. The transdermal dosage form of claim 11, wherein the transdermal dosage form comprises a reservoir comprising the opioid or a pharmaceutically salt acceptable thereof, to the opioid antagonist in the form of free base and to the pharmaceutically acceptable salt of an antagonist opioid 19. The transdermal dosage form of claim 11, wherein the transdermal dosage form is a Polymer matrix type transdermal dosage form. 20. The transdermal dosage form of claim 11, wherein the transdermal dosage form is a Transdermal dosage form in drug type adhesive. 21. The transdermal dosage form of claim 1, wherein the pharmaceutically opioid or salt acceptable from it is selected from among the members from the group consisting of alfentanil, allylprodin, alphaprodin, anileridine, benzylmorphine, benzitramide, buprenorphine, butorphanol, clonitacene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dihydromorphone, dihydroisomorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafethyl butyrate, dipipanone, eptazocine, etoheptacin, ethylmethylthiambutene, ethylmorphine, etonitacene, etorphine, dihydroetorphine, fentanyl, heroin, hydrocodone, Hydromorphone, Hydromorphone, Hydroxipetidine, Isometadone, ketobemidone, levorphanol, levofenacylmorphan, lofentanyl, meperidine, meptacinol, methazocine, methadone, metopon, morphine, mirofin, narcein, nicomorphine, norlevorphanol, normetadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum, paregoric, pentazocine, pheadoxone, phendimetracine, phendimetrazone, pheromorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptacin, promedol, properidine, propoxyphene, propylhexedrine, sulfentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof and mixtures of any two or more thereof. 22. The transdermal dosage form of claim 21, wherein the pharmaceutically active opioid or salt acceptable thereof is oxycodone or a pharmaceutically salt Acceptable of it. 23. The transdermal dosage form of claim 21, wherein the pharmaceutically active opioid or salt acceptable thereof is hydrocodone or a pharmaceutically salt Acceptable of it. 24. The transdermal dosage form of claim 21, wherein the pharmaceutically active opioid or salt acceptable thereof is buprenorphine or a pharmaceutically salt Acceptable of it. 25. The transdermal dosage form of claim 21, wherein the pharmaceutically active opioid or salt acceptable thereof is fentanyl or a pharmaceutically salt acceptable of it. 26. The transdermal dosage form of claim 25, wherein the opioid antagonist in the form of a Free base is naltrexone and the pharmaceutically acceptable salt is naloxone HCl. 27. The transdermal dosage form of claim 25, wherein the opioid antagonist in the form of a Free base is naloxone and the pharmaceutically acceptable salt is Naltrexone HCl. 28. The transdermal dosage form of claim 25, wherein the opioid antagonist in the form of a Free base is nalmefene and the pharmaceutically acceptable salt is naloxone HCl. 29. The transdermal dosage form of claim 25, wherein the opioid antagonist in the form of a Free base is nalmefene and the pharmaceutically acceptable salt is Naltrexone HCl. 30. The transdermal dosage form of claim 11, wherein the opioid antagonist in the form of a free base is selected from among the group members that It consists of cyclazocine, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine, cyclazacin and levalorfan. 31. The transdermal dosage form of claim 30, wherein the opioid antagonist in the form of a free base is selected from among the group members that It consists of naloxone, naltrexone and nalmefene. 32. The transdermal dosage form of claim 11, wherein the pharmaceutically acceptable salt of a opioid antagonist is a pharmaceutically acceptable salt of a opioid antagonist selected from group members consisting of cyclazocine, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine, cyclazacin and levalorfan.

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33. The transdermal dosage form of claim 32, wherein the pharmaceutically acceptable salt of a opioid antagonist is a pharmaceutically acceptable salt of a opioid antagonist selected from group members It consists of naloxone, naltrexone and nalmefene. 34. Kit that is to treat pain in a patient and understands: a) the transdermal delivery device of the claim 11; Y b) a printed set of instructions that indicate how to use the transdermal dosage form to Treat the pain 35. Use of an opioid or salt pharmaceutically acceptable thereof, an opioid antagonist in form of a free base and an opioid antagonist in the form of a pharmaceutically acceptable salt for the manufacture of a form Transdermal dosage to treat or prevent pain in a patient.